Protein Arginine Deiminases, are present in humans and a variety of other organisms and consist of a group of isozymes (PADs 1, 2, 3, 4, and 6) that catalyze the Ca2+-dependent conversion of arginine to citrulline in a variety of proteins (e.g., histones H2A, H3, and H4).
Protein Arginine Deiminase 4 (PAD4) is a 663 amino acid, 74 kDa, human protein whose deiminating activity (Arg→Cit) appears to be dysregulated in rheumatoid arthritis (RA). Although speculative, it has been suggested that an elevated PAD4 activity causes an overproduction of deiminated proteins that initially leads to a break in self tolerance, and eventually causes the immune system to attack its own tissues. As such, PAD4 represents a novel therapeutic target for RA and inhibition of PAD4 can reduce the levels of deiminated proteins and consequently suppress the immune response directed towards these antigens.
A similar role for PAD2 is thought to play a role in the onset and progression of multiple sclerosis (MS).
Additionally, Protein Arginine Deiminases are thought to play a regulatory role in a number of human cell signaling pathways, including differentiation, apoptosis, and gene transcription.
As such, a need exists for development of PAD-targeted therapeutics, including synthesis methods for novel PAD inhibitors and inactivators. In addition, a need exists for methods of using such inhibitors and inactivators.